Sperm count in Swedish clinical stage I testicular cancer patients following adjuvant treatment.

BACKGROUND: Little is known regarding sperm production following adjuvant treatment in testicular cancer (TC) clinical stage I (CS I) patients. PATIENTS AND METHODS: A total of 182 TC patients aged 18-50 years were prospectively included during 2001-2006 at any given time within 5 years of orchiectomy. Semen samples were delivered postorchiectomy but before further treatment, 6, 12, 24, 36 and 60 months (T0-T60) after completed therapy. Total sperm number (TSN) and sperm concentration (SC) were used as measurements of testicular function. Four groups according to treatment modality were identified; Radiotherapy; To a total dose of 25.2 Gy to the infradiaphragmal paraaortic and ipsilateral iliac lymph nodes (RT, N = 70), one cycle of adjuvant BEP (bleomycin, etoposide, cisplatin, 5 day regimen) (BEP, N = 62), one cycle of adjuvant carboplatin AUC 7 (Carbo, N = 22), and patients managed by surveillance (SURV, N = 28). RESULTS: In the cross-sectional analysis, a significant but transient drop in mean TSN and mean SC (T0-T60) was seen at T6 after radiotherapy. Apart from a significant increase in mean SC at T12 compared with baseline, no significant differences were observed in the other treatment groups. In 119 patients delivering 3 or more samples, values in TSN and SC were rather stable over time. Azoospermic patients (N = 11) were observed in most treatment groups except for in the BEP group. During follow-up, one azoospermic patient belonging to the Carbo group became normospermic. CONCLUSIONS: No clinically significant long-term effect on TSN or SC associated with adjuvant treatment in TC CSI patients was found. However, as patients may have low sperm counts before orchiectomy as well as after adjuvant treatment, we offer sperm banking before orchiectomy as assisted reproductive measures may be necessary regardless of treatment given.

Maternal polycystic ovary syndrome and the risk of autism spectrum disorders in the offspring: a population-based nationwide study in Sweden.

Although many studies indicate the interplay of genetic and environmental factors in the etiology of autism spectrum disorder (ASD), our limited understanding of the underlying mechanisms hampers the development of effective ways of detecting and preventing the disorder. Recent studies support the hypothesis that prenatal androgen exposure contributes to the development of ASD. This would suggest that maternal polycystic ovary syndrome (PCOS), a condition associated with excess androgens, would increase the risk of ASD in the offspring. We conducted a matched case-control study nested within the total population of Sweden (children aged 4-17 who were born in Sweden from 1984 to 2007). The sample consisted of 23 748 ASD cases and 208 796 controls, matched by birth month and year, sex and region of birth. PCOS and ASD were defined from ICD codes through linkage to health-care registers. Maternal PCOS increased the odds of ASD in the offspring by 59%, after adjustment for confounders (odds ratio (OR) 1.59, 95% confidence interval (CI) 1.34-1.88). The odds of offspring ASD were further increased among mothers with both PCOS and obesity, a condition common to PCOS that is related to more severe hyperandrogenemia (OR 2.13, 95% CI 1.46-3.10). Risk estimates did not differ between sexes. In conclusion, children of women with PCOS appear to have a higher risk of developing ASD. This finding awaits confirmation, and exploration of potentially underlying mechanisms, including the role of sex steroids in the etiology of ASD.

Inhibin B concentration is predictive for long-term azoospermia in men treated for testicular cancer.

Azoospermia is a serious potential side effect following treatment for testicular cancer (TC). Our purpose was to examine possible predictors of long-term azoospermia in TC survivors. Ejaculates and blood samples were obtained from 217 patients at post-orchidectomy but before further treatment (T0 ) and/or at one or more of the time points 6, 12, 24, 36-60 months after treatment (T6 , T12 , T24 , T36-60 ). All patients delivered ejaculates at T36-60 , of which 117 also had confirmed presence of spermatozoa in the ejaculate at T0 , enabling longitudinal analyses. Types of therapy, cryptorchidism and Inhibin B before and after treatment were evaluated in relation to risk of azoospermia at T36 . Inhibin B levels at T6 , T12 and T24 were predictors of azoospermia at T36 with cut-off levels at 49.7, 55.9 and 97.8 ng/L respectively (sensitivity 100%, specificity 57-78%). The frequency of azoospermia in all patients at T36-60 was 7.8% (95% CI 4.9-12%). As compared to surveillance patients, only those receiving >4 cycles of chemotherapy or ≥4 cycles of chemotherapy + radiotherapy (RT) had increased risk of long-term azoospermia (63% vs. 4.4% in the surveillance group; p = 0.0018). In conclusion, all patients with sperm production at post-orchidectomy but before further treatment and Inhibin B >56 ng/L 12 months after treatment had sperm production 3 years post-treatment. Eight per cent of TC survivors had azoospermia 3-5 years post-treatment, with highest risk in those receiving >4 cycles of chemotherapy or ≥4 cycles of chemotherapy in combination with RT.

Sex differences in cortical thickness and their possible genetic and sex hormonal underpinnings.

Although it has been shown that cortical thickness (Cth) differs between sexes, the underlying mechanisms are unknown. Seeing as XXY males have 1 extra X chromosome, we investigated the possible effects of X- and sex-chromosome dosage on Cth by comparing data from 31 XXY males with 39 XY and 47 XX controls. Plasma testosterone and estrogen were also measured in an effort to differentiate between possible sex-hormone and sex-chromosome gene effects. Cth was calculated with FreeSurfer software. Parietal and occipital Cth was greater in XX females than XY males. In these regions Cth was inversely correlated with z-normalized testosterone. In the motor strip, the cortex was thinner in XY males compared with both XX females and XXY males, indicating the possibility of an X-chromosome gene-dosage effect. XXY males had thinner right superior temporal and left middle temporal cortex, and a thicker right orbitofrontal cortex and lingual cortex than both control groups. Based on these data and previous reports from women with XO monosomy, it is hypothesized that programming of the motor cortex is influenced by processes linked to X-escapee genes, which do not have Y-chromosome homologs, and that programming of the superior temporal cortex is mediated by X-chromosome escapee genes with Y-homologs.

Specific localization of RBM1a in the nuclei of all cell types except elongated spermatids within seminiferous tubules of the human.

Recent studies have indicated that at least three regions (AZF a-c) on the long arm of the Y-chromosome code for factors are involved in spermatogenesis. One of the candidate genes in the AZFb region is RBM1a, coding for a protein with an RNA binding motif. In this study, poly clonal antibodies raised against a 15 amino acid peptide, corresponding to residues 263-304 of the deduced amino acid sequence of RBM1a, has been used to localize the RBM1a protein in the human testis. Immunohistochemistry on normal human testis using this RBM1a antibody, localized the antigen to the nuclei of spermatogonia, primary spermatocytes, and round spermatids but not to the nuclei of elongated spermatids. The antibody also specifically identified the nuclei of Sertoli cells, although the fluorescence was not as strong as in the germ cell nuclei it identified. No specific fluorescence was seen in the nuclei of either peritubular, endothelial or Leydig cells. Western blot of normal human testicular tissue using the anti-RBM1a antibody gave rise to a single specific band of approximately 55 kDa, corresponding to the expected size of RBM1a. In view of its expression in germ cells, and because RBM1a has an RNA binding domain, RBM1a may be involved in RNA processing, such as RNA splicing or RNA export which are events necessary for normal spermatogenesis.

A novel mutation (N233K) in the transactivating domain and the N756S mutation in the ligand binding domain of the androgen receptor gene are associated with male infertility.

OBJECTIVE: Resistance to androgens has been suggested as a possible cause of male infertility. This hypothesis is based mainly on binding studies in genital skin fibroblasts but the molecular evidence is sparse. DESIGN: Molecular studies of the androgen receptor gene were performed in 10 azoo- or oligozoospermic men, presenting with clinical signs of low androgen activity-poor virilization and high serum LH despite elevated testosterone levels, but without genital malformations. PATIENTS: Ten men with serum LH >10 IU/l and testosterone >30 nmol/l as well as a low sperm concentration < 20 x 106/ml. MEASUREMENTS: Genomic DNA was prepared from peripheral leucocytes and PCR-amplification of the coding region of androgen receptor was performed, followed by direct sequencing. Identified mutations were reconstructed by site-directed mutagenesis and the functional properties of the mutants were analysed, using transient expression in COS-1 cells and subsequent transactivation assays. Hormone binding assays were performed in genital skin fibroblasts from the patients. RESULTS: Two of the 10 men were shown to have a mutation in the androgen receptor gene. Subject 1, who presented with azoospermia, serum testosterone (T) 50 nmol/l and LH 20 IU/l, had a mutation in exon 1, changing amino acid asparagine 233 to lysine (N233K). In fibroblasts cultured from genital skin, the receptor affinity for 5alpha-dihydrotestosterone (DHT) was normal as compared to healthy controls, but the receptor-hormone complex was thermolabile at 42 degrees C. Subject 2 exhibited severe oligozoospermia and a similar endocrine pattern (T = 50 nmol/l and LH = 25 IU/l). He had a mutation in exon 5 changing asparagine 756 to serine (N756S). The affinity for DHT in cultured genital fibroblasts from this patient was reduced. Transactivation was abnormal for both mutants, N233K reaching 46% and N756S 38% of wild type activity when stimulated with 10 nmol/l DHT. CONCLUSIONS: Androgen receptor mutations may affect sperm production without resulting in genital malformations. Thus, in infertile men with a clinical presentation of poor androgen activity and an endocrine profile compatible with androgen resistance, mutations in the androgen receptor should be taken into consideration.

Interrelationships among lipoprotein levels, sex hormones, anthropometric parameters, and age in hypogonadal men treated for 1 year with a permeation-enhanced testosterone transdermal system.

Serum lipoproteins and cardiovascular risk are affected by endogenous and exogenous sex hormones. As part of a multicenter evaluation of a permeation-enhanced testosterone transdermal system (TTD), the interrelationships among serum lipoproteins, hormone levels, anthropometric parameters, and age were investigated in 29 hypogonadal men. Subjects (aged 21-65 yr) were first studied during prior treatment with im testosterone esters (IM-T), then during an 8-week period of androgen withdrawal resulting in a hypogonadal state (HG), and finally during a 1-yr treatment period with the TTD. Compared with treatment with IM-T, the HG period produced increases in high density lipoprotein [HDL; 12.0 +/- 1.6% (+/-SEM); P<0.001] and total cholesterol (4.2 +/- 1.9%; P: = 0.02) and a decrease in the cholesterol/HDL ratio (-9.7 +/- 2.8%; P = 0.02). Compared with the HG period, TTD treatment produced decreases in HDL (-7.6 +/- 2.5%; P = 0.002) and increases in the cholesterol/HDL ratio (9.0 +/- 2.5%; P = 0.01) and triglycerides (20.7 +/- 6.4%; P: = 0.03). Small decreases in total cholesterol (-1.2 +/- 1.8%; P: = 0.1) and low density lipoprotein (-0.8 +/- 2.6%; P = 0.07) were also observed during TTD, but did not reach statistical significance. Likewise, there were no significant differences between the IM-T and TTD treatments. Serum HDL levels showed a strong negative correlation with body mass index and other obesity parameters in all three study periods (r < -0.45; P < 0.02). During treatment with TTD, serum testosterone levels also correlated negatively with body mass index (r = -0.621; P < 0.001). As a consequence of these relationships, a positive trend was observed between HDL and testosterone levels during TTD treatment (r = 0.336; P = 0.07). Interestingly, the changes in lipoprotein levels during TTD treatment indicated a more favorable profile (decrease in cholesterol and low density lipoprotein levels) with increasing age of the patients. In hypogonadal men the effects of transdermal testosterone replacement on serum lipoproteins appear consistent with the physiological effects of testosterone in eugonadal men.

Malignant human renin producing paraganglionoma-localization with 123I-MIBG and treatment with 131I-MIBG.

A 22-year-old woman presenting severe hypertension and hypokalaemia is described. Initial evaluation showed a large tumour localized at the position of the left adrenal gland. Subsequent surgery temporarily relieved all signs and symptoms caused by the tumour. The symptoms relapsed after a 2-year disease-free interval. At re-evaluation, the tumour was shown to produce an uncontrolled secretion of renin, thus triggering aldosterone-dependent hypertension. This report describes the diagnosis, treatment and clinical course of this unique patient with a malignant paraganglionoma of adrenal origin.

Pharmacokinetics, efficacy, and safety of a permeation-enhanced testosterone transdermal system in comparison with bi-weekly injections of testosterone enanthate for the treatment of hypogonadal men.

The pharmacokinetics, efficacy, and safety of the Androderm testosterone (T) transdermal system (TTD) and intramuscular T enanthate injections (i.m.) for the treatment of male hypogonadism were compared in a 24-week multicenter, randomized, parallel-group study. Sixty-six adult hypogonadal men (22-65 years of age) were withdrawn from prior i.m. treatment for 4-6 weeks and then randomly assigned to treatment with TTD (two 2.5-mg systems applied nightly) or i.m. (200 mg injected every 2 weeks); there were 33 patients per group. Twenty-six patients in the TTD group and 32 in the i.m. group completed the study. TTD treatment produced circadian variations in the levels of total T, bioavailable T, dihydrotestosterone, and estradiol within the normal physiological ranges. i.m. treatment produced supraphysiological levels of T, bioavailable T, and estradiol (but not dihydrotestosterone) for several days after each injection. Mean morning sex hormone levels were within the normal range in greater proportions of TTD patients (range, 77-100%) than i.m. patients (range, 19-84%). Both treatments normalized LH levels in approximately 50% of patients with primary hypogonadism; however, LH levels were suppressed to the subnormal range in 31% of i.m. patients vs. 0% of TTD patients. Both treatments maintained sexual function (assessed by questionnaire and Rigiscan) and mood (Beck Depression Inventory) at the prior treatment levels. Prostate-specific antigen levels, prostate volumes, and lipid and serum chemistry parameters were comparable in both treatment groups. Transient skin irritation from the patches was reported by 60% of the TTD patients, but caused only three patients (9%) to discontinue treatment. i.m. treatment produced local reactions in 33% of patients and was associated with significantly more abnormal hematocrit elevations (43.8% of patients) compared with TTD treatment (15.4% of patients). Gynecomastia resolved more frequently during TTD treatment (4 of 10 patients) than with i.m. treatment (1 of 9 patients). Although both treatments seem to be efficacious for replacing T in hypogonadal men, the more physiological sex hormone levels and profiles associated with TTD may offer possible advantages over i.m. in minimizing excessive stimulation of erythropoiesis, preventing/ameliorating gynecomastia, and not over-suppressing gonadotropins.

Effects of testosterone replacement with a nongenital, transdermal system, Androderm, in human immunodeficiency virus-infected men with low testosterone levels.

Although weight loss associated with human immunodeficiency virus (HIV) infection is multifactorial in its pathogenesis, it has been speculated that hypogonadism, a common occurrence in HIV disease, contributes to depletion of lean tissue and muscle dysfunction. We, therefore, examined the effects of testosterone replacement by means of Androderm, a permeation-enhanced, nongenital transdermal system, on lean body mass, body weight, muscle strength, health-related quality of life, and HIV-disease markers. We randomly assigned 41 HIV-infected, ambulatory men, 18-60 yr of age, with serum testosterone levels below 400 ng/dL, to 1 of 2 treatment groups: group I, two placebo patches (n = 21); or group II, two testosterone patches designed to release 5 mg testosterone over 24 h. Eighteen men in the placebo group and 14 men in the testosterone group completed the 12-week treatment. Serum total and free testosterone and dihydrotestosterone levels increased, and LH and FSH levels decreased in the testosterone-treated, but not in the placebo-treated, men. Lean body mass and fat-free mass, measured by dual energy x-ray absorptiometry, increased significantly in men receiving testosterone patches [change in lean body mass, +1.345 +/- 0.533 kg (P = 0.02 compared to no change); change in fat-free mass, +1.364 +/- 0.525 kg (P = 0.02 compared to no change)], but did not change in the placebo group [change in lean body mass, 0.189 +/- 0.470 kg (P = NS compared to no change); change in fat-free mass, 0.186 +/- 0.470 kg (P = NS compared to no change)]. However, there was no significant difference between the 2 treatment groups in the change in lean body mass. The change in lean body mass during treatment was moderately correlated with the increment in serum testosterone levels (r = 0.41; P = 0.02). The testosterone-treated men experienced a greater decrease in fat mass than those receiving placebo patches (P = 0.04). There was no significant change in body weight in either treatment group. Changes in overall quality of life scores did not correlate with testosterone treatment; however, in the subcategory of role limitation due to emotional problems, the men in the testosterone group improved an average of 43 points of a 0-100 possible score, whereas those in the placebo group did not change. Red cell count increased in the testosterone group (change in red cell count, +0.1 +/- 0.1 10(12)/L) but decreased in the placebo group (change in red cell count, -0.2 +/- 0.1 10(12)/L). CD4+ and CD8+ T cell counts and plasma HIV copy number did not significantly change during treatment. Serum prostate-specific antigen and plasma lipid levels did not change in either treatment group. Testosterone replacement in HIV-infected men with low testosterone levels is safe and is associated with a 1.35-kg gain in lean body mass, a significantly greater reduction in fat mass than that achieved with placebo treatment, an increased red cell count, and an improvement in role limitation due to emotional problems. Further studies are needed to assess whether testosterone supplementation can produce clinically meaningful changes in muscle function and disease outcome in HIV-infected men.

'Potency': the validation of information from a self-administered questionnaire using objective measurements of night-time erections and test-retest reliability.

OBJECTIVE: To assess the validity and reliability of a questionnaire assessing 'physiological potency'. PATIENTS AND METHODS: The study comprised 89 patients with prostate cancer and 43 men without; the latter were attending a consultation clinic because of problems with erection. All men answered three questions assessing erectile rigidity during sexual activity, morning and spontaneous erections. In the questionnaire, 'potency' was defined as erectile rigidity 'sufficient for intercourse most of the time' or better. 'Potency' in one or more of the three aspects of erection was defined as 'physiological potency'. The patients with prostate cancer answered the questionnaire twice with a 3-week interval. The men attending the consultation clinic underwent two nights of erectile monitoring (using the RigiScan device) and the minimum criterion for RigiScan potency was defined as 55% rigidity at both tip and base. RESULTS: The test-retest assessment showed 93% conformity in the questionnaire diagnosis of 'physiological potency/impotence' between the tests. The sensitivity and specificity of the questionnaire assessment compared with the RigiScan method were 40% and 100%, respectively, when the question assessing sexually stimulated erectile rigidity was used alone. Using 'physiological potency', the sensitivity increased to about 60% without jeopardizing the specificity, and when men reporting depression were excluded from the analysis, the sensitivity increased to about 80%. CONCLUSIONS: The test-retest reliability of the questionnaire was satisfactory. Using questions in a self-administered questionnaire, 'physiological impotence' can be diagnosed with complete and 'physiological potency' with 60-80% sensitivity. The sensitivity of the self-assessment for 'potency' depended on the number of questions asked and the proportion of men reporting depression.

Androgen replacement in the treatment of Klinefelter's syndrome: efficacy and safety of a nonscrotal permeation-enhanced testosterone transdermal system.

OBJECTIVE: To report the efficacy and safety of a permeation-enhanced nonscrotal testosterone transdermal (TTD) system for the treatment of Klinefelter's syndrome. METHODS: Fifteen male patients with Klinefelter's syndrome, including 12 patients who received previous intramuscular (IM) treatment with testosterone esters, were part of the study population from three phase III clinical studies; 13 completed the studies. Patients applied two TTD systems nightly for 6 months or more. Nocturnal erections were assessed by RigiScan monitoring; sexual function was evaluated by using the Watts and Davidson questionnaires. Hypogonadal symptoms were determined by direct patient questioning. RESULTS: Mean morning serum testosterone levels increased to within normal range in all 13 patients (from 5.9 +/- 3.2 nmol/L at hypogonadal baseline to 22.3 +/- 5.6 nmol/L at 6 months). Luteinizing hormone levels decreased to within normal range in six patients and showed clinically significant decreases in four of the other seven patients (from 25 +/- 12 IU/L at hypogonadal baseline to 17 +/- 11 IU/L at 6 months). Nocturnal erections improved significantly during TTD system therapy in comparison with the hypogonadal state. Patient self-reported measures of sexual functioning were comparable to those during prior IM testosterone treatment and better than during the hypogonadal state. Hypogonadal symptoms decreased during TTD therapy in comparison with hypogonadal baseline. No clinically significant changes were noted in prostate volume, prostate-specific antigen, or lipid values. Three patients experienced anxiety or depression during TTD treatment, requiring discontinuation of therapy in one case and use of antidepressants in the other two. CONCLUSION: The testosterone patches were generally well tolerated in all patients. The nonscrotal TTD system for testosterone replacement is a safe and effective treatment for patients with Klinefelter's syndrome.

Androgens and abdominal obesity.

Central or visceral obesity is recognized as a main risk factor for cardiovascular disease and type 2 diabetes mellitus. The co-existence of visceral obesity, increased blood lipid levels, hypertension and impaired glucose tolerance defines the metabolic syndrome that today is widely recognized as one of the prime factors behind cardiovascular morbidity and mortality. Endocrine disorders such as insulinoma, hypothyroidism and hypercortisolism are known to cause obesity. However, it is only hypercortisolism that is associated with increased abdominal fat accumulation. Recently, new findings have shed light on subtle endocrinopathies that are prevalent in individuals presenting with the metabolic syndrome. Such derangements are of borderline character and often fall within the normal reference range. Intervention studies demonstrate that correction of relative hypogonadism in men with visceral obesity and other manifestations of the metabolic syndrome seem to decrease the abdominal fat mass and reverse the glucose intolerance, as well as lipoprotein abnormalities in the serum. Further analysis of the underlying mechanism has also disclosed a regulatory role for testosterone in counteracting visceral fat accumulation. Longitudinal epidemiological data demonstrates that relatively low testosterone levels are a risk factor for development of visceral obesity. The primary event that triggers the initial development of visceral obesity is not known, but it seems plausible that increased activity in the hypothalamus-pituitary-adrenal axis can be of major importance.

Complementary deoxyribonucleic acid cloning and characterization of a putative human axonemal dynein light chain gene.

Immotile Cilia Syndrome (ICS) is characterized by recurrent sinus and lung infections, bronchiectasis, and sperm immotility. Nasal cilia and sperm tails in patients with ICS exhibit a variety of ultrastructural defects, often including shortening or absence of the inner dynein arms. Immotile mutant strains of Chlamydomonas, a biflagellated algae, have ultrastructural defects similar to those seen in patients with this clinical disorder. Furthermore, splice-site mutations in the Chlamydomonas inner dynein arm gene (p28) are associated with impaired flagellar motility. We therefore hypothesized that the human homologue of the Clamydomonas dynein p28 gene would be an attractive candidate gene for patients with ICS. Accordingly, we cloned the full length complementary DNA (cDNA) and genomic clone by screening of appropriate libraries and databases, using the protein sequence of the Chlamydomonas p28 gene. The human homologue is encoded by a 921 bp transcript (accession no. AF006386) with an open reading frame of 257 amino acids. Using somatic cell and radiation hybrid panels, the hp28 gene was mapped to human chromosome 1p35.1. The hp28 cDNA probe hybridizes to sequences in all species on a zoo blot containing genomic DNA from yeast to human. Northern blot analysis reveals two hp28 gene transcripts, 0.9 and 2.5 kb, in many tissues. The 0.9 kb transcript is expressed at a 20-fold higher level than the 2.5-kb transcript in the testis. The entire gene is included in a 20-kb EcoRI genomic fragment and has 7 exons and 6 introns. Cloning of the hp28 cDNA and mapping of the intron-exon junctions should now make it possible to test whether a subset of ICS is a consequence of mutations in the human axonemal dynein light chain gene hp28.

Factors associated with waning sexual function among elderly men and prostate cancer patients.

PURPOSE: We identified factors that affect sexual function in men 50 to 80 years old and, therefore, may confound the comparison among groups of elderly men. In particular, we identified factors that may influence a comparison between prostate cancer patients and the general population, or confound the relationship when comparing subgroups of patients in nonrandomized studies. MATERIALS AND METHODS: A questionnaire, including the Radiumhemmet Scale of Sexual Function and modules assessing potential risk factors for waning sexual function, was sent to 431 patients 50 to 80 years old with prostate cancer diagnosed 1.5 to 2 years previously in the Stockholm area (Sweden) and a reference group of 435 age matched randomly selected men. RESULTS: Factors associated with physiological impotence included prostate cancer (relative risk 1.9), diabetes mellitus (relative risk 2.3), myocardial infarction (relative risk 1.5), medication with diuretics (relative risk 1.5), hydrogen blockers (relative risk 2.3) and warfarin type anticoagulants (relative risk 1.7). Patients treated for prostate cancer were more likely to be physiologically impotent compared to those with no initial treatment, and this was true for all treatment protocols after adjustment for confounding factors. Men treated with radical prostatectomy were more likely to be physiologically impotent than men treated with external beam radiation therapy (relative risk 1.5). CONCLUSIONS: Waning sexual function in the prostate cancer patients was largely due to side effects of the treatment and this could not be explained by confounding factors. In particular, confounding could not explain the greater risk of impotence after radical prostatectomy compared to external beam radiation therapy.

Prostate size in hypogonadal men treated with a nonscrotal permeation-enhanced testosterone transdermal system.

OBJECTIVES: This study examined the effects of testosterone replacement using a nonscrotal testosterone transdermal (TTD) system on prostate size and prostate-specific antigen (PSA) levels in hypogonadal men. METHODS: As part of an open-label, multicenter study, prostate volume as measured by transrectal ultrasound and PSA were assessed in 29 hypogonadal men during treatment with intramuscular testosterone enanthate (+TE), followed by 8 weeks of androgen withdrawal (-T), and then during 1 year of therapy with Androderm Testosterone Transdermal System, a nonscrotal permeation-enhanced TTD system (+TTD). RESULTS: Mean prostate volume decreased significantly from the +TE period (17 g) compared with the -T period (14 g) (P < 0.001). Prostate volume increased significantly from the -T period compared with the +TTD period (18 g) (P < 0.001). Maximum prostate size, comparable to that measured during +TE (P = 0.125), was reached by month 3 of +TTD therapy; prostate volume did not increase further during the remaining 9 months of +TTD therapy. Prostate volume correlated with age (P < 0.01) during all three periods of observation (+TE: r = 0.69; -T: r = 0.64; and +TTD: r = 0.55). No patient developed symptomatic benign prostatic hyperplasia during the treatment period. PSA levels decreased during androgen withdrawal compared with levels measured during +TE treatment (P < 0.001) and rose with resumption of androgen therapy with TTD (P < 0.006). However, PSA levels during +TTD replacement remained significantly lower (P < 0.001) than during +TE replacement. CONCLUSIONS: Physiologic testosterone replacement in hypogonadal men was achieved using the TTD system. Prostate size during therapy with TTD was comparable to that reported for normal men. In these men treated with TTD, PSA levels were also within the normal range.

Long-term efficacy and safety of a permeation-enhanced testosterone transdermal system in hypogonadal men.

OBJECTIVE: An important aim in treating male hypogonadism is restoration of physiological concentrations of testosterone and its metabolites. We have assessed hormone levels, pharmacokinetics and clinical response, including safety, of a permeation-enhanced testosterone transdermal system (TTD) in the treatment of hypogonadal men for a 12-month period. DESIGN: Open-label, multicentre study with four consecutive periods: Period I (3 weeks)--evaluation of patients' current androgen therapy, which consisted primarily of testosterone enanthate injections (mean dose 229 mg; mean interval 26d); Period II (8 weeks)--androgen washout; Period III (3-4 weeks)--single-dose pharmacokinetic studies of TTD systems; Period IV (12 months)--efficacy, safety, and steady-state pharmacokinetic evaluation of TTD systems (5 mg/day nominal delivery rate of testosterone). Results from Periods I, II, and IV were compared. PATIENTS: Thirty-seven hypogonadal men 21-65 years old enrolled; 34 entered Periods III and IV; 29 (9 primary, 20 secondary hypogonadism) completed the study. Four patients withdrew because of adverse events (Period II, one; Period IV, three). MEASUREMENTS: Morning serum levels of total testosterone (T), bioavailable testosterone (BT), dihydrotestosterone (DHT), and oestradiol (E2) levels. Circadian pattern of T profiles and 24-hour time-average T level. LH levels in patients with primary hypogonadism. Reduction of hypogonadal symptoms. Safety assessments including skin tolerability, prostate parameters, lipid profile, and systemic parameters. RESULTS: Twelve months of TTD therapy normalized morning serum T levels in 93% of patients, and produced greater than 80% normalization of BT, DHT and E2 levels. The TTD system mimicked the circadian variation in T levels seen in healthy young men and normalized 24-hour time-average T levels in 86% of patients. Luteinizing hormone was suppressed in 8 of 9 men with primary hypogonadism, and normalized in 5 of these. Subjective symptoms of hypogonadism, including decreased libido and fatigue, showed improvement after 2-4 weeks of TTD treatment in most patients. The majority of adverse events were local skin reactions, and 3 patients (9%) discontinued the study for this reason. Prostate assessments showed a lower prostate-specific antigen level during TTD therapy compared to IM injections (0.66 vs 1.00 microgram/l P < 0.001), while prostate size did not differ significantly between the two treatment regimens. CONCLUSIONS: The permeation-enhanced testosterone transdermal system produces physiological levels and circadian patterns of testosterone, and its metabolites, in hypogonadal men. Although transient erythema and itching is commonly reported, the TTD is generally well tolerated by most patients. This system offers a new treatment option for testosterone replacement therapy that results in physiological serum levels of sex hormones in hypogonadal men.

Waning sexual function--the most important disease-specific distress for patients with prostate cancer.

The objective was to investigate how prostate cancer and its treatment affects sexual, urinary and bowel functions and to what extent eventual complications cause distress. A questionnaire was sent to 431 men aged 50-80 years with prostate cancer diagnosed in 1992 in the Stockholm area (Sweden) and 435 randomly selected men with a similar age distribution. Sexual function, as compared with their youth, was diminished in a majority of all men. The prostate cancer patients were, however, more likely to report low frequency and/or intensity in all aspects of sexual function. A majority of the men were distressed by a waning sexual capacity. The proportion of men with prostate cancer who were severely distressed owing to a decline in sexual function was larger than in the reference group. The willingness to trade off an intact sexual function for long-term survival varied considerably among the men in the reference group. Urinary and bowel symptoms were less common than a waning sexual function in both groups, and few appeared to be severely distressed by urinary or bowel symptoms. A decline in sexual functions was the most common cause of disease-specific distress in men with prostate cancer.